4-Aryl-1-(indanmethyl dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl) piperidines tetrahydropyridines or piperazines

ABSTRACT

4-Aryl- 1 -(indanmethyl, dibydrobenzofuramethyl or dihydrobenzotbiophenemethyl) piperidine, -tetrabydropyridine or -piperazine compounds of general formula (I)  
                 
 
     wherein one of X and Y is CH 2 , and the other one is CH 2 , O or S; Z is N, C, CH or COH; Ar is an optionally substituted aryl group; R 1  is hydrogen, alkyl, cycloalkyl, cycloakylalkyl, aryl, arylalkyl, acyl, thioacyl, alkylsulfonyl, trifloromethylsulfonyl, arylsulfonyl, a group R 9 VCO— where V is O or S and R 9  is alkyl or aryl, or a group R 10 R 11 NCO or R 10 R 11 NCS— wherein R 10  and R 11  are hydrogen, alkyl or aryl, or R 10  and R 11  are linked to form a ring R 2  is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; or R 1  and R 2  are linked to form a ring; R 3 —R 5  are hydrogen, halogen, alkyl, alkylcarbonyl, phenylcarbonyl, alkoxy, alkylthio, hydroxy, alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkylaLkyl or nitro; R 6  and R 7  are bydrogen or alkyl or they are linked to constitute a 3-7-membered ring; R 8  is hydrogen or alkyl; have effects at central serotonergic receptors and are therefore useful in the treatment of certain psychic and neurologic disorders.

[0001] This is a conlinualion of international application Ser. No.PCT/DK95/00230, filed Jun. 8. 1995.

FIELD OF THE INVENTlON

[0002] The present invention relates to a novel class of4-aryl-1-(indaniiethyl, diliydrobenzofuranmelhyl ordihydrobenzothiophenemethyl)pipcridine, -letrahydropyridine or-piperazine compounds having effects at central serotonergic receptors.These methylamine compounds are therefore useful in the treatment ofcertain psychic and neurologic disorders.

BACKGROUND OF THE INVENTION

[0003] A few aminomethylindan, -dihydrobenzofurane anddihydrobenzothiophene compounds are known from the prior art.

[0004] So, EP patent 0 281 261 discloses 1-aminomethylindan,3-aminomethylbenzofurane and 3-aminomthylbenzothiophene derivatives witha hydroxy group or a substituted hydroxy group in the 6-position (indan)or 5-position (benzofurane, benzothiophene). These compounds were foundto show central dopamine agonist activity, in particular to show effectat presynaptic dopamine receptors.

[0005] In U.S. Pat. No. 4,500,543 certain 1-aminomethylphtalanecompounds are said to show adrenergic effects and, accordingly,antihypertensive and heart rate decreasing properties. Said patentgenerically covers compounds having substituents in the 5-, 6- and/or7-position.

[0006] EP0325963 A1 discloses among other compounds a class of1-aminomethyl indan compounds in which the aminomethyl group mayconstitute a 1-pyrrolylmethyl group which is substituted with thienyl orphenyl. The compounds are claimed to be α₂ antagonists useful in thetreatment of depression, metabolic disorders, glaucoma, migraine andhypertension.

[0007] Furthermore, EP 0490772 A1 describes i.a. a class of4-benzofuranyl- or 4-benzodioxanyl-1-indanylmethyl piperazine compoundsbeing S-HT_(1A) ligands.

[0008] EP 0428437 generically covers a very broad class of1,2-benzoisoxazole compounds including certain3-[1[-(1-indanyl)methyl]1,2-benzoisoxazoles. However, only one suchcompound is examplified and in that case without giving any data. Thecompounds are said to show dopamine and serotonin antagonisticactivities.

[0009] U.S. Pat. No. 3,886,168 relates to 1-[(indan-1-yl)methyl]piperidine compounds having antihypertensive activity.

[0010] Various effects are known with respect to compounds which areligands at the different serotonin receptor sub-types. As regards the5-HT_(2A) receptor, which was previously referred to as the 5-HT₂receptor, the following effects have e.g. been reported:

[0011] The 5-HT_(2A) antagonist ritanserin (Meert, T. F.; Janssen, P. A.J. Drug. Dev. Res. 1989, 18, 119.) has been shown to be effective in thetreatment of anxiety and depression presumably through improvement ofthe sleep quality. Furthermore, selective, centrally acting 5-HT_(2A)antagonists have been shown to have an effect towards the negativesymptoms of schizophrenia and to reduce extrapyramidal side-effectscaused by treatment with classical neuroleptics ill schizophrenicpatients (Gelders, Y. G., British J. Psychiatry, 1989, 155. (suppl.5),33). Finally, selective 5-HT_(2A) antagonists could be effective in theprophylaxis and treatment of migraine since it is known that 5-HT isinvolved in migraine attacks. Th links between 5-HT and migraine attacksare several and they suggest a number of mechanisms whereby 5-HT may beinvolved (Scrip Report; “Migraine—Current trends in research andtreatment”; PJB Publications Ltd.; May 1991).

[0012] The serotonin 5-HT_(2A) antagonist, MDL 100,907 (Sorensen, S. M.et al., J. Pharmacol. Exp. Ther. 1993, 266, 684-691), and certaincompounds within series of 1-phenylindoles (WO 93/12790) and3-phenylindole derivatives (WO 93/14758) have shown anti-psychoticactivity in animal models with indication of no liability to causeextrapyramidal side effects (EPS).

[0013] Clinical studies of known 5-HT_(1A) partial agonists such as e.g.buspirone,8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-(dione, gepirone, 4,4-dimethyl- 1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedione, andipsapirone,2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]1,2-benzothiazol-3(2H)-one-1,1-dioxide,have shown that 5-HT_(1A) partial agonists are useful in the treatmentof anxiety disorders such as generalised anxiety disorder, panicdisorder, and obsessive compulsive disorder (Glitz, D. A., Pohl R.,Drugs 1991, 41, 11). Preclinical studies indicate that also fullagonists are useful in the treatment of the above mentioned anxietyrelated disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).

[0014] There is also evidence, both clinical and preclinical, in supportof the beneficial effect of 5-HT_(1A) partial agonists in the treatmentof depression, impulse control disorders and alcohol abuse (van Hest,Psychopharmacol., 1992, 107, 474; Schipper et al, HumanPsychopharmacol., 1991, 6, S53; Cervo el al, Eur. J. Pharm., 1988, 158,53; Glitz and Poh, Drugs 1991, 41, 11; Grof el al., Int. Clin.Psychopharmacol. 1993, 8, 167-172; Ansseau et al., HumanPsychopharmacol. 1993, 8, 279-283).

[0015] 5-HT_(1A) agonists and partial agonists inhibit isolation-inducedaggression in male mice indicating that these compounds are useful inthe treatment of aggression (Sanchéz et al., Psychopharmacology, 1993,110, 53-59).

[0016] Furthermore, 5-HT_(1A) ligands have been reported to showantipsychotic effect in animal models (Wadenberg and Ahlenius, J.Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol. & Toxicol., 1989,64, 3; Lowe el al., J. Med. Chem., 1991, 34, 1860, New et al., J. Med.Chem., 1989, 32, 1147;and Martin el al., J. Med. Chem., 1989, 32, 1052).

[0017] Recent studies also indicate that 5-HT_(1A) receptors areimportant in the serotonergic modulation of haloperidol-inducedcatalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al.Pharmacol. Biochem. & Behav. 1994, 47, 509-513) suggesting that5-HT_(1A) agonists are useful in the treatment of EPS induced byconventional antipsychotic agents such as haloperidol.

[0018] 5-HT_(1A) agonists have shown neuroprotective properties inrodent models of focal and global cerebral ischaemia and may, therefore,be useful in the treatment of ischaemic disease states (Prehn, Eur. J.Pharm. 1991, 203, 213).

[0019] Pbarmacological studies have been presented which indicates that5-HT_(1A) antagonists are useful in the treatment of senile dementia(Bowen et al, Trends Neur. Sci. 1992, 15, 84).

[0020] Both in animal models and in clinical trials it has been shownthat 5-HT_(1A) agonists exert antihypertensive effects via a centralmechanism (Saxena and Villalon, Trends Pharm. Sci. 1990, 11, 95; Gillisel al J. Pharm. Exp. Ther. 1989, 248, 851). 5-HT_(1A) ligands may,therefore, be beneficial in the treatment of cardiovascular disorders.

[0021] 5-HT reuptake inhibitors are well known antidepressant drugs.

[0022] As 5-HT_(1A) and 5-HT2A receptor ligand classes of compounds and5-HT reuptake inhibitors have different activities in different animalmodels predictive of anxiolytic and antiaggressive effects (Perregaardet al., Recent Developments in Anxiolytics. Current Opinion inTherapeutic Patents 1993, 1, 101-128) and/or in models predictive ofeffects in other psychic disorders it might also be highly beneficial totreat complex states of anxiety, depression, or other psychic disorderswith a drug which have combined scrolonergic effects.

SUMMARY OF THE INVENTION

[0023] If has now been found that certain novel 4-aryl-1-(indanmethyl,dihydrobenzofuranmethyl or dihydrobenzothiophenemethyl)piperidines,-tetrahydropyridines or -piperazines interact potently with centralserotonergic receptors, in particular with the 5-HT_(1A) and/or the5-HT_(2A) receptors.

[0024] Accordingly, the present invention relates to novel compounds ofthe formula I.

[0025] wherein one of X and Y is CH₂ and the other one is selected fromthe group consisting of CH₂, O, and S; the dotted line, emanaling fromZ, indicates an optional bond; when it does not indicate a bond Z is N,CH or COH; and when it indicates a bond Z is C; Ar is phenyl, 2-thienyl,3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl,3-indolyl,1-indol-2-onyl, 3-indol-2-onyl, 2- or 3-benzofuranyl, 2- or3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substitutedwith halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, loweralkylsulfonyl, cyano, trifluoromethyl, trifluromethylsulfonyloxy,cycloalkyl, cycloalkyl-lower-alkyl, nitro, amino, lower alkylamino,di-lower alkylamino, acylamino or C₁₋₂ alky-lenedioxy; R¹is hydrogen,lower alkyl, lower alkenyl, lower alkynyl, cycloalk(en)yl,cycloalk(en)yl-lower alk(en/yn)yl, aryl, aryl-lower alkyl, acyl,thioacyl, lower alkylsulfonyl, trifluorometbylsulfonyl, arylsulfonyl, R¹is a group R⁹VCO— where V is O or S and R⁹ is lower alkyl, cycloalkyl,cycloalkyl-lower-alkyl or aryl, or R¹ is a group R¹⁰R¹¹NCO— orR¹⁰R¹¹NCS— wherein R¹⁰ and R¹¹are independently hydrogen, lower alkyl,cycloalkyl, cycloalkyl-lower-alkyl or aryl, or R¹⁰ and R¹¹ together withthe N-atom to which they are linked, form a pyrrolidinyl, piperidinyl orperhydroazepin group; R² is hydrogen, lower alklyl, cycloalkyl orcycloalkyl-lower-alkyl; or R¹ and R² together with the N-alom to whichtlhey are linked form a group,

[0026] wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH_(2;) and m is14-, inclusive; R³-R⁵ are independently hydrogen, halogen, lower alkyl,lower alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano,trifluoromethyl, cycloalkyl, cycloalkyl-lower-alkyl or nitro; R⁶ and R⁷are each hydrogen or lower alkyl or they are linked together toconstitute a 3-7-membered carbocyclic ring; R⁸ is hydrogen or loweralkyl; any alkyl, cycloalkyl or cycloalkylalkyl group present beingoptionally substituted with one or two hydroxy groups, which again areoptionally esterified with an aliphatic or aromatic carboxylic acid; andany aryl substituent present being optionally substituted with halogen,lower alkyl, lower alkoxy, lower alkylthio, hydroxy, loweralkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy,cycloalkyl, cycloalkyl-lower-alkyl or nitro; and pharmaceuticallyacceptable acid addition salts thereof.

[0027] The compounds of the invention have been found to show potentaffinity to 5-HT_(1A) receptors and/or to 5-HT_(2A) receptors. Inaddition to the eject at these receptor subtypes, certain of the,present compounds also show 5-HT reuptake inhibiting effect.

[0028] Accordingly, the compounds of the invention arc considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders, aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep.

[0029] In another aspect the invention provides a pharmaceuticalcomposition comprising at least one compound of Formula I as definedabove or a pharmaceutically acceptable acid addition salt thereof orprodrug thereof in a therapeutically effective amount and in combinationwith one or more pharmaceutically acceptable carriers or diluents.

[0030] In a further aspect the present invention provides the use of acompound of Formula I as defined above or an acid addition salt orprodrug thereof for the manufacture of a pharmaceutical preparation forthe treatment of the above mentioned disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Compounds of general Formula I exist as optical isomers thereofand such optical isomers are also embraced by the invention.

[0032] Prodrugs of the compounds of general Formula I are also embracedby the invention.

[0033] The term cycloalkyl designates a corbocyclic ring having 38carbon atoms, inclusive, or a bicyclic or tricyclic carbocycle, such asadamantyl.

[0034] The term lower alkyl refers to a branched or unbranched alkylgroup having from one to six carbon atoms inclusive, such as methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-1-propyl. The terms lower alkoxy, lower alkylthio, loweralkylsulfonyl, lower alkylamino, lower alkylcarbonyl, etc. designatesuch groups in which the alkyl group is lower alkyl as defined above.Similarly, lower alkenyl and alkynyl, respectively, designate suchgroups having from two to six carbon atoms, inclusive. Preferred groupsare those having up to four carbon atoms.

[0035] The term aryl refers to a mono- or bicyclic carbocyclic orheterocyclic aromatic group, such as phenyl, indolyl, thienyl,pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzofuranyl, benzothienyl, pyridyl, naphthyl and furanyl, in particularphenyl, pyrimidyl, indolyl, and thienyl.

[0036] Halogen means fluoro, chloro, bromo or iodo.

[0037] As used herein the term acyl refers to a formyl, loweralk(en/yn)ylcarbonyl, arylcarbonyl, aryl-lower alk(en/yn) ylcarbonyl,cycloalkylcarbonyl, or cycloalkyl-lower-alk(en/yn)ylcarbonyl group.

[0038] The term thioacyl is the corresponding acyl group in which thecarbonyl group is replaced with a thiocarbonyl group.

[0039] The expression alk(en/yn)yl means that the group may be an alkyl,alkenyl, or alkynyl group.

[0040] In Formula I, X is preferably CH or S and Y is preferably CH₂ andmost preferably they are both CH₂.

[0041] R¹ is preferably acyl, lower alkyl, lower alkoxy, a groupR¹⁰R¹¹NCO— or R¹⁰R¹¹NCS— wherein R¹⁰ is hydrogen, lower alkyl,cycloalkyl, cycloalkyl-lower-alkyl or aryl and R¹¹ is hydrogen or loweralkyl or R¹⁰ and R¹¹ together with the N-atom to which they are linked,form a pyrrolidinyl, piperidinyl or perhydroazepin group. Mostpreferably, R¹ is formyl, acetyl, methylaminocarbonyl,methylaminothiocarbonyl, dimethylaminocarbonyl,dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl,cyclopropylcarbonyl, methyl, pyrrolidinyl-carbonyl or4-fluorophenylaminocarbonyl. R² is preferably hydrogen or lower alkyl,most preferably hydrogen or methyl, or R¹ and R² are linked together toform a 5-7 membered unsubstituted lactam ring or a pyrrolidinyl,piperidinyl or perhydroazepin.

[0042] R³-R⁵ are preferably hydrogen, fluoro, chloro, bromo, methyl,trifluoromethyl or acetyl and R⁶-R⁸ are preferably all hydrogen.

[0043] Finally, Ar is preferably phenyl, 3-indolyl, 1-indolyl, orpyrimidyl or phenyl, 3-indolyl, 1-indolyl or pyrimidyl substituted withhalogen.

[0044] A preferred subclass of compounds are those wherein R¹ is acetyland R² is 11 and in particular such compounds wherein Ar is indolyl orphenyl substituted with halogen, especially chloro. If Ar is 3-indolylit is preferably substituted in the 6-position and if it is phenyl, itis preferably substituted in the 4-position.

[0045] Another preferred subclass of compounds of the invention arethose wherein R¹ is a group R¹⁰R¹¹NCO— or R¹⁰R¹¹NCS— wherein R¹⁰ ishydrogen, lower alklyl, cycloalkyl, cycloalkyl-lower-alkyl or aryl andR¹¹ is hydrogen or lower alkyl and R² is hydrogen.

[0046] In a further preferred subclass of compounds R¹ is hydrogen,lower alkyl or lower alkylsulfonyl in particular methyl ormethylsulfonyl and R² is hydrogen or lower alklyl, in particular methyl,or R¹ and R² are linked together to form a pyrrolidinon ring or apyrrolidinyl ring.

[0047] Preferred compounds are:

[0048] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperidine.

[0049] (+)-1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0050] (−)-1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine

[0051]1-(6-Acetylamino-5-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0052]1-(6-Acetylamino-4-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0053]1-(6-Acetylamino-4-bromoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0054]1-(6-Acetylamino-4-nitroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0055]1-(6-Acetylamino-4-cyanoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0056]1-(6-Acetylamino-5-chloroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0057]1-(6-Acetylamino-5-bromoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0058]1-(6-Acetylamino-5-cyanoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0059]1-(6-Acetylamino-7-chloroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0060]1-(6-Acetylamino-7-fluoroindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0061]1-(5-Acetyl-6-acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0062]1-(6-Acetylamino-1-methylindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0063] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-fluorophenyl) piperidine.

[0064] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-fluorophenyl) piperidine.

[0065] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-methylphenyl) piperidine.

[0066]1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-dimethylaminophenyl)piperidine.

[0067] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-aminophenyl) piperidine.

[0068]1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-trifluoromethylphenyl)piperidine.

[0069] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperazine.

[0070]1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0071]1-(6-Acetylamino-1,3-dihydroisobenzofuran-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0072] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl) piperazide.

[0073] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-chlorophenyl) piperazine.

[0074] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-chlorophenyl) piperazine.

[0075]1-(6-Acetylaminoindan-1-ylmethyl)4-(4-trifluoromethylsulfonyloxyphenyl)piperazine.

[0076] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl)piperazine.

[0077] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl)piperidine.

[0078] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-methoxyphenyl) piperazine.

[0079] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine.

[0080] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.

[0081] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyrimidyl) piperidine.

[0082] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyrimidyl) piperazine.

[0083] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-pyridinyl) piperazine.

[0084] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-thienyl) piperidine.

[0085] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-thienyl) piperidine.

[0086] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-thienyl) piperazine.

[0087] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-naphthyl) piperidine.

[0088] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-naphthyl) piperidine.

[0089] 1-(6-butanoylaminoindan-1-ylmethyl)-4(4-fluorophenyl) piperidine

[0090] 1-(6-Formylaminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperidine.

[0091] 1-(6-Formylaminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperazine.

[0092]4-(4-Fluorophenyl)-1-(6-methansulfonylaminoindan-1-ylmethyl)piperidine.

[0093]1-(6-Cyclopropylcarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0094]1-(6-Cyclopentylcarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0095]4-(4-Fluorophenyl)-1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidine.

[0096]1-[6-(4-Fluorophenyl)aminocarbonylaminoindan-1-ylmethyl]-4-(4-fluorophenyl)piperidine.

[0097]4-(4-Fluorophenyl)-1-(6-methylaminothiocarbonylaminoindan-1-ylmethyl)piperidine.

[0098]1-(6-Dimethylaminocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0099]1-(6-Dimethylaminothiocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0100] 4-(4-Fluorophenyl)-1-[6-(1-pyrrolidinyl)carbonylaminoindan-1-ylmethyl]piperidine.

[0101]1-(6-Aminocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine.

[0102] 1-(6-Ethoxycarbonylaminoindan-1-ylmethyl)-4-(4-4-fluorophenyl)piperidine.

[0103]1-[6-(N,N-dimethylamino)indan-1-ylmethyl]-4-(4-fluorophenyl)piperidine.

[0104]3-[1-(5-Acetylamino-2,3-dibydrobenzothiophen-3-ylmelhyl)piperidin-4-yl]-5chloro-1H-indole.

[0105] 3-[1-(5-Acetylamino-2,3-dihydrobenzothiopben-3-yl methyl)-1,2,3,6-tetrahydropyridin-4-yl]-5 -chloro-1H-indole.

[0106]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-fluoro-1H-indole.

[0107] 3-[1-(6-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl-1,2,3,6-tetrahydropyridin-4-yl]-5-fluoro-1H-indole.

[0108]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole.

[0109]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.

[0110]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1-metbyl-1H-indole.

[0111]1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.

[0112]1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole.

[0113]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole.

[0114]4-(4-Fluorophenyl)-1-[6-(1-pyrrolidin-2-onyl)indan-1-ylmethyl]piperidine.

[0115]4-(4-Fluorophenyl)-1-[6-(1-piperidin-2-onyl)indan)-1-ylmelhyl]piperidine.

[0116]1-[6-(4-Fluorophenylamino)indan-1-ylmethyl]-4-(4-fluorophenyl)piperidine

[0117]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]1-6-chlorobenzothiophene.

[0118]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin4-yl]-6-chlorobenzothiophene.

[0119]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chlorobenzothiophene.

[0120]2-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chlorobenzothiophene.

[0121]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chlorobenzofurane.

[0122]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indol-2-one

[0123]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1-methyl-1H-indol-2-one.

[0124]3-[1-(6-Acetylaminoindan-1-ylmethyl)1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1-methyl-1H-indol-2-one.

[0125]2-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole.

[0126]1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indol-2-one.

[0127] 3-[1-(6-Methylaminokarbonylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole.

[0128] 3-[1-(6-Methylaminokarbonylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-chloro-1H-indole.

[0129] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-bromophenyl) piperidine.

[0130]1-(6-Acetylaminoindan-1-ylmethyl)-4-hydroxy-4-(4-chlorophenyl)piperidine.

[0131]1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl)piperazine.

[0132] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-chloro-3-thienyl)piperidine.

[0133] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chloro-2-thienyl)piperidine.

[0134]1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperidine.

[0135]1-(6-Acetylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine.

[0136]1-(6-Methylaminocarbonylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine.

[0137]1-(6-Acetylaminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine.

[0138]1-(6-Acetylaminoindan-1-ylmethyl)-4-acetyloxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine.

[0139]5-chloro-1-[1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidin-4-yl]-1H-ind0le

[0140] The acid addition salts of the invention are pharmaceuticallyacceptable salts of the compounds of Formula I formed with non-toxicacids. Exemplary of such organic salts are those with maleic, fumaric,benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acelic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmilic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, and theophyl-line aceticacids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, bydrobromic, sulfuric, sulfamic, phosphoric, and nitricacids.

[0141] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route, for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0142] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to100 mg.

[0143] The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

[0144] Thc invention moreover relates to a method for the preparation ofthe novel 4-Aryl-1-[amino(indan, dihydrobenzofuran ordihydrobenzothiophene)methyl] piperidines, -tetrahydropyridines or-piperazines of Formula I, comprising:

[0145] a) reacting an amino derivative of the following Formula II:

[0146] wherein R²-R⁸, X, Y, Z, Ar, and the dotted line are as previouslydefined, with a reagent of the formula R^(1′)-hal or R¹-OCOR, in whichformulas hal is halogen, R is alkyl, aryl or alkoxy and R^(1′) is acyl,thioacyl, a group R⁹VCO—, or a group R¹⁰R¹¹NCO— or R¹⁰R¹¹NCS— where R⁹,V, R¹⁰ and R¹¹are as previously defined except that neither R¹⁰ nor R¹¹may be hydrogen, or with a lower alkylsulfonyl halogenide,trifluoromethylsulphonyl halogenide or an isocyanate or thioisocyanateof the formula R¹⁰—N═C═O or R¹⁰—N═C═S wherein RIO is as previouslydefined;

[0147] b) in order to prepare a compound of Formula I wherein R¹ islower alk(en/yn)yl, cycloalk(en)yl, cycloalk(en) yl-lower alk(en/yn)ylor aryl-lower alkyl, alkylating an amino derivative of Formula II withan alkylating agent such as an aklkylhalogenide R¹-hal, a mesylate R¹OSO₂CH₃, a tosylate R¹OSO₂C₆H₄—CH₃, or a similar alkylating reagent withsuitable leaving groups, R¹ being lower alkyl, lower alkenyl, loweralkynyl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl or aryl-loweralkyl;

[0148] c) reducing the tetrahydropyridinyl double bond in derivatives ofthe following Formula III:

[0149] wherein R¹-R⁸, X, Y and Ar are as previously defined; or

[0150] d) alkylating an arylpiperazine, arylpiperidine, oraryltetrahydropyridine of the formula V with an alkylating derivative ofthe formula IV:

[0151] wherein R¹-R^(8,) X, Y, Z, Ar, and the dotted line are aspreviously defined, and w is a leaving group such as eg. halogen,mesylate, or tosylate; or

[0152] e) in order lo obtain to form a compound of Formula I in whichthe substituents R¹ and R² together constitute a ring, ring closure of aderivative of Formula VI:

[0153] in which R³-R⁸, X, Y, Z. Ar, m, Q, T and the dotted line are aspreviously defined and w is a leaving group such as halogen, mesylate,or losylate;

[0154] f) in order to obtain a compound of Formula I in which R1 islower alk(en/yn)yl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl oraryl-lower alkyl, reducing the carbonyl group of an amide derivative ofthe following Formula VII:

[0155] wherein R²-R^(8,) X, Y. Z, Ar and the dotted line are aspreviously defined and R^(1′″) is such a group that the group R^(1′″)constitutes a lower alk(en/yn)yl, cycloalk(en)yl, cycloalk(en)yl-loweralk(en/yn)yl or aryl-lower alkyl as embraced by the definition of R¹; or

[0156] g) introducing a substituent R³, R⁴ or R⁵ by reacting a compoundof the following Formula VIII:

[0157] wherein one of R³-R⁵ is hydrogen and the other two are thecorresponding R³, R4 or R⁵ as previously defined and R¹, R^(2,) R⁶-R⁸,X, Y, Z, Ar and the dotted line are as previously defined, by using areactive reagent such as a halogen or a halogenating agent, asulfonating agent, a nitration agent or a reactive agent generatingcarbonium ions (RCO+, R+) wherein R is alkyl alkynyl, aryl cycloalkyl,or cycloalk (en/yn))yl; or

[0158] h) reducing the double bond in a compound of the followingFormula IX:

[0159] wherein R¹-R⁸, X. Y, Z, and Ar are as previously defined and oneof the two dotted lines indicates a double bond; or

[0160] i) reducing thc amide carbonyl in a compound of the followingFormula X:

[0161] wherein R¹-R⁵, R⁸, X, Y, Z, Ar and the dotted line are aspreviously defined.

[0162] whereupon the compound of Formula I is isolated as the free baseof a pharmaceutically acceptable acid addition salt thereof.

[0163] The reaction in Method a) is conveniently performed at lowtemperature (eg. below room temperature) in an inert solvent such asacetone, dichloromethane, tetrahydrofuran or dimethoxyethane whenreactive carboxylic acid chlorides, isocyanates, or isothiocyanates areused. Formulated amines are prepared from the corresponding amines byreaction in formic acid, with esters of formic acid, or by reaction withmixed formic acid anhydride prepared in situ. Generally reactiontemperatures are between 0° C. and the boiling point of the formylprecursor compounds.

[0164] The alkylations according in Method b) and d) are generallyperformed by refluxing in a suitable solvent such as acetone, methylisobutyl ketone, tetrahydrofuran, ioxane, ethanol or 2-propanol in thepresence of a base such as triethylamine or potassium carbonate.

[0165] The reductions of double bonds according to Methods c) and h) aregenerally performed by catalytic hydrogenation at low pressure (<3 atm.)in a Parr apparatus, or by using reducing agents such as diborane ininert solvents such as tetrahydrofuran, dioxane, or diethyl ether.

[0166] The reductions according to Methods f) and i) are generallyperformed by use of LiAIH_(4,) AIH₃ or diborane in an inert solvent suchas tetrahydrofuran, dioxane, or diethyl ether at room temperature or ata slightly elevated temperature.

[0167] The halogenation according to Method g) is generally performed byuse of chlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide oranother halogen precursor molecule, conveniently in the presence of acatalyst such as Fe ions or a mineral acid.

[0168] 1-Unsubstituted 4-arylpiperazines or Formula V (Z═N) are eithercommercially available or may be synthesized from the correspondinganilines and N′,N′-bis(2-chloroethyl)amine by refluxing in high boilingsolvents as chlorobenzene typically for 2-3 days according to methodsdescribed by Martin et al. J. Med. Chem. 1989, 32 152-1056.

[0169] 4-Arylpiperidines of formula V (Z═CH) are either commerciallyavailable or prepared as described in eg. U.S. Pat. No. 2,891,066;McElvain ce al. J. Amer. Chem. Soc. 1950, 72, 3134; Bally et al Chem.Ber. 1887, 20, 2590. The Corresponding4-aryl-1,2,3,6-tetrahydropyridines of Formula V (Z═C) are prepared fromN-protected 4-piperidones by addition of properly substituted aryllithium or magnesium halides followed by acid catalyzed waterelimination. The N-protecting group (carbamate, benzyl, sulfonyl,acetyl) is finally removed in a conventional manner.

[0170] Synthesis of 3-(4-piperidinyl)-1H-indoles and3-(1,2,3,6-tetrahydropyridin-4-yl)-1 H-indoles is described in theExperimental Section.

[0171] Key intermediates such as 1-indancarboxylic acid (V. Asham and W.H. Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al. Helv. Chim.Acta 1982, 33, 325-343), and 5-nitro-3-benzothiophenecarboxylic acid (EPPat. Appln. No. 88-301073 CA(110(9):75302y (1988) and references citedtherein) were prepared according to well-known literature procedures.

[0172] Experimental Section

[0173] In the following the invention is further illustrated by exampleswhich, however, may not be construed as limiting.

[0174] In all the Examples, melting points were determined on a BuchiSMP-20 apparatus. Melting points are given as uncorrected values. ¹H NMRspectra were recorded at 250 MHz on a Bruker AC 250 spectrometer.Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) were usedas solvents. TMS was used as internal reference standard. Chemical shiftvalues are expressed in ppm-values. The following abbreviations are usedfor multiplicity of NMR signals: s=singlet, d=doublet, t=triplet,q=quartet, qui=quinict, h=hepict, dd=double doublet, dt=double triplet,dq=double quartet, t=triplet of triplets, m=multiplet.

EXAMPLE 1

[0175] 6-Nitro-1-indancarboxylic acid, 1a

[0176] A solution of 1-indancarboxylic acid (30 g), prepared accordingto the method of Hansen et al. Helv. Chim. Acta 1982, 33, 325-343, indichloromethane (50 ml) was mixed with concentrated sulphuric acid (300ml) at −10° C. A mixture of 100% HNO₃ (11.4 g) in concentrated H₂SO₄ (96ml) was added dropwise under vigorous stirring below −10° C. Afterstirring for one hour at 10° C., the mixture was poured onto ice.Extraction with ethyl acetate (2×30 ml), drying (anb. MgSO₄) and finallyevaporation of the organic solvent afforded 42 g of the title compound.Mp 126-130° C.

[0177] 5-Nitro-3-benrzothiophenearboxylic acid was prepared from3-bromo-5-nitrobenzothiophene via the corresponding3-cyanobenzothiophene derivative according to EP Pat. No. 88-301073 (CA110(9):75203y (1988), J. Amer. Chem. Soc. 1948, 70, 1955, and J. Chem.Soc.(c) 1967, 1899.

EXAMPLE 2 (Method i)

[0178] 1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperidine, 2a

[0179] Dimethylformamide (DMF, 1 ml) was added to a solution of6-nitro-1-indancarboxylic acid, 1a (13 g) and thionylchloride (18 ml) indichloromethane (125 ml). The mixture was heated to reflux for 4 hours.Toluene was added and volatile material was evaporated in vacua. Thethus obtained carboxylic acid chloride was dissolved in dichloromethane(100 ml) and added dropwise to a solution of 4-(4-fluoro phenyl)piperidine (19.5 g) and triethylamine (7 ml) in dichloromethane (100 ml)at 0-5° C. The mixture was stirred at room temperature for another 1.5hours. Water was added, the organic phase separated, washed with brine,dried (anh. MgSO₄), filtered, and dichloromethane evaporated in vacuoleaving the crude 6-nitroindan-1-carboxamide derivative as an oil (35g). Purification by column chromatography on silica gel (eluted with a1:1 mixture of ethyl acetate and heptane) yielded 12 g of the purecarboxamide as an oil. All of this oil was dissolved in refluxing 90%,ethanol (350 ml). Fe-powder (10 g) and concentrated aqueous HCl (1 ml)were added successively in small portions during 10 minutes. Theresulting mixture was refluxed for another 2.5 hours. Inorganic saltswere filtered off while still hot and ethanol evaporated in vacua.Diluted aqueous NH₄OH was added until pH>9. Extraction with ethylacetate (2×200 ml) and working-up as above of the organic phase afforded8 g of the 6-aminoindan-1-carboxamide derivative. Mp: 144-45° C. To asuspension of LiAIH₄ (2.7 g) in dry tetrahydrofuran (THF, 125 ml ) wasadded dropwise a solution of all of the carboxamide in THF (125 ml). Themixture was gently refluxed for 2 hours. After cooling to 10° C. water(10 ml) and a 15% aqueous NaOH solution were cautiously added to destroyexcess LiAIH₄. Inorganic salts were filtered off and washed extensivelywith THF. The combined THF solutions were evaporated leaving 6.5 g ofthe title compound 2a as an oil. The hydrochloride salt crystallizedfrom 2-propanol. Mp: 198-201° C. ¹H NMR (DMSO-d₆): δ 1.85-2.40(m, 6H);2.60-2.90 (m, 3 H); 3.00-3.15 (m, 3 H); 3.35 (broad s, 3 H); 3.45-3.60(m, 2 H); 3.65-3.75 (m, 1 H); 6.45 (d, 1 H); 6.50 (s, 1 H); 6.95 (d, 1H); 7.15 (t, 2 H); 7.25-7.35 (m, 2 H).

[0180] In a similar manner the following aniline derivatives wereprepared:

[0181] 1-(6-Aminoindan-1-ylmethyl)-4-(2-metboxyphenyl) piperazine, 2b asan oil

[0182] 1-(6-Aminoindan-1-ylmethyl)-4-(2-chlorophenyl) piperazine, 2c asan oil.

[0183] 1-(6-Aminoindan-1-ylmethyl)-4-(3-chlorophenyl) piperazine, 2d asan oil.

[0184] 1-(6-Aminoindan-1-ylmethyl)-4-(4-chlorophenyl) piperazine, 2c,mp: 98-109° C.

[0185]1-(5-Amino-2,3-dihydrobenzothiophen-3-ylmethyl)-4-(4-fluorophenyl)piperidine,2f as an oil.

[0186]1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine,2g, mp: 78-84° C.

[0187] 1-(6-Aminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl) piperazine, 2h, mp: 156-158° C. (washed with diethyl ether). ¹H NMR (CDCl₃): δ1.70-1.90 (m, 1 H); 2.20-2.30 (m, 1 H); 2.45 (dd, 1 H); 2.55-2.75. (m, 6H); 2.75-2.90 (m, 2 H); 3.20 (t, 4 H); 3.20-3.35 (m, 1 H); 3.55 (broads, 2 H); 6.50 (dd, 1 H); 6.70-6.80 (m, 2 H); 6.90-7.00 (m, 2 H); 7.25(d, 1 H).

[0188]1-(6-Aminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine, 2i asan oil

[0189]1-(6-Aminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)-piperidine,2j as an oil

[0190] 1-(6-Aminoindan-1-ylmethyl)-4-(4-methylphenyl) piperidine, 2k asan oil.

[0191]1-(6-Aminoindan-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine,2l as an oil.

EXAMPLE 3 (Method 3i)

[0192] 1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperazine, 3a

[0193] 1-Indancarboxylic acid (20 g), DMF (2 ml), and thionylchloride(53 g) in dichloromethane (250) were refluxed for 4 hours. Volatilematerial was evaporated in vacuo and remaining thionylchloride wasremoved by evaporation with toluene in vacuo. The remaining cartoxylicacid chloride was dissolved in dichloromethane (200 ml) and addeddropwise to a solution of 1-(4-fluorophenyl)piperazine (58 g) indichloromethane (200 ml) at 0-5° C. After stirring for 1.5 hours at roomtemperature, the organic phase was washed successively with water andbrine and finally work-up as above of the organic phase yielded 66 gcrude carboxamide. Purification by column chromatography on silica gel(eluted with ethyl acetate/beptane 1:1) yielded 36 g of crystallineproduct with mp: 119-124° C. All of this product was dissolved inconcentrated H₂SO₄ (170 ml) at −10° C. A mixture of 100% HNO₃ (6.9 g) inconcentrated H₂SO₄ (55 ml) was added dropwise under vigorous stirringbelow −10° C. The mixture was stirred for another hour at −5° C. Themixture was poured onto ice (500 g) and a 1:1 mixture of dichloromethaneand ethyl acetate (300 ml) was added. This organic phase was separatedand washed with diluted Na₂CO₃ solution (2×200 ml) and brine (200 ml).Work-up of the organic phase as above yielded 35 g of the crude6-nitroindan-1-carboxamide derivative as an oil. The crude product wasdissolved in 90%, ethanol at reflux. Fe-powder (31.5 g) and concentratedaqueous HCl (3.1 ml) were added successively in small portions during 30minutes. The resulting mixture was refluxed for another 2.5 hours.Inorganic salts were filtered off while still hot and ethanol evaporatedin vacuo. Diluted aqueous NH₄OH was added until pH>9. Extraction withdichloromethane (2×200 ml) and working-up as above of the organic phaseafforded 31 g of crystalline 6-aminoindan-1-carhoxamide derivative. Mp:143-149° C. To a suspension of LiAIH 4 (10.4 g) in dry THF (400 ml) wasadded dropwise a solution of all of the carhoxamide in THF (400 ml). Themixture was gently refluxed for 2.5 hours. After cooling to 15° C. water(40 ml ) and a 15% aqueous NaOH solution (10.4 ml) were cautiously addedto destroy excess LiAIH₄. Inorganic salts were filtered off and washedextensively with THF. The combined THF solutions were evaporated leaving23.7 g of the title compound 3a as an oil.

EXAMPLE 4 (method a)

[0194] 1-(6-Acetylaminoindan-1-ylmethyl)4-(4-fluorophenyl)piperidline 4a

[0195] To a solution of1-(6-aminoindan-1-ylmethyl)4-(4-fluorophenyl)piperidine, 2a (6.5 g) andtriethylamine (3 ml) in dichloromethane (150ml) cooled to (0° C. wasadded dropwise a solution of acetylchloride (1.7 g) in dichloromethane(50 ml). The mixture was stirred for one hour at room temperature. Water(500 ml) was added, the organic phase separated, washed with brine (2×50ml) and finally worked-up as above. The thus isolated crude titleproduct was purified by column chromatography on silica gel (eluted witha mixture of ethyl acetate/heptane/ triethylamine 75:25:4).Recrystallization from diethyl ether yielded 7.7 g of pure titlecompound 4a. Mp: 159-162° C. ¹H NMR (CDCl₃): δ 1.70-1.90 (m, 5 H);2.00-2.15 (m, 1 H); 2.15 (s, 3 H); 2.20-2.30 (m, 1 H); 2.35-2.50 (m, 2H); 2.60 (dd, 1 H); 2.70-2.90 (m, 2 H); 2.95-3.15 (m, 2 H); 3.45 (qui, 1H); 6.95 (t, 2 H); 7.05-7.25 (m,5 H); 7.55 (s, 1 H)

[0196] In a corresponding manner, thc following acylamino,thioacylamino, and sulfonylamino derivatives were prepared:

[0197] 1-(6-Acetylaminoindan-1-ylmetbyl)-4-(4-fluorophenyl) piperazine4b, mp:179-187° C. (ethanol). ¹H NMR (DMSO-d₆): δ 1.70-1.85 (m, 1 H);2.00 (s, 3 H); 2.10-2.25 (m, 1 H); 2.35 (dd, 1 H), 2.50-2.60 (m, 5 H);2.65-2.90 (m, 2 H); 3.10 (t, 4 H); 3.35 (qui, 1 H); 6.90-7.10 (m, 5H);7.30 (d, 1 H); 7.60 (s, 1 H); 9.75 (s, 1 H)

[0198] 1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-4-(4-fluorophenyl)piperidine 4c, mp: 140-142° C. (washed with diethyl ether). ¹H NMR(DMSO-d₆): δ 1.55-1.75 (m, 4 H); 1.95 (s, 3 H); 1.90-2.05 (m, 1 H);2.05-2.20 (dt, 1 H); 2.35 (dd, 1 H); 2.40-2.55 (m, 3 H); 2.95 (d, 1 H),3.15 (d, 1 H); 3.20-3.35 (m, 1 H); 3.45 (t 1 H); 3.55-3.70 (m, 1 H);7.05-7.15 (m, 3 H); 7.25-7.35 (m, 3 H); 7.65 (s, 1 H); 9.85 (s,1 H)

[0199] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl) piperazine4d, mp: 191-194° C. (acetone). ¹H NMR (CDCl₃): δ 1.80-1.95 (m, 1H); 2.10(s, 3 H); 2.20-2.35 (m,1 H); 2.45 (dd, 1 H); 2.60-2.70 (m, 5 H);2.80-2.95 (m, 2 H); 3.15 (t, 4 H); 3.35 (qui, 1 H); 6.85 (d, 2 H);7.05-7.25 (m, 5 H); 7.55 (s, 1 H);

[0200] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(3-chlorophenyl) piperazine4e., mp: 176-178° C. (acetone). ¹H NMR (CDCl₃): δ 1.75-1.90 (m, 1 H),2.15 (s, 3 H); 2.20-2.35 (m, 1 H); 2.45 (dd, 1 H);2.60-2.75 (m, 5H);2.75-2.95 (m, 2 H); 3.20(t, 4 H); 3.35 (qui, 1 H); 6.80 (d, 2 H); 6.85(s, 1 H); 7;10-7.30 (m, 4 H); 7.55 (s, 1 H)

[0201] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(2-chlorophenyl) piperazine,hydrochloride, 4f mp: 195-203° C. (acetone). ¹H NMR (DMSO-d₆): δ 2.00(s, 3 H); 2.00-2.15 (m, 1 H); 2.30-2.45 (m, 1 H); 2.75-2.95 (m, 2 H);3.20-3.80 (m, 1 H); 7.05-7.40 (m, 5 H); 7.45 (d, 1 H); 7.65 (s, 1 H);10.00 (s, 1 H); 10.95 (broad s, 1 H)

[0202] 1-(6-Acetylaminoindan-1-ylmethyl)4-(2-methoxyphenyl) piperazinie,oxalate 4g, mp: 210-213° C. (acetone/ethanol 1:1), ¹H NMR (DMSO-d₆): δ1.85-2.00 (m, 1 H); 2.05 (s, 3H); 2.25-2.40 (m, 1 H); 2.65-3.05 (m, 3H); 3.25 (broad s, 8 H); 3.45-3.60 (m, 1 H); 3.80 (s, 3 H); 6.85-7.05(m, s 4 H); 7.15 (d, 1 H); 7.30 (d, 1 H); 7.60 (s, 1 H); 9.90 (s, 1 H)

[0203] 1-(6-Acetylaminoindan-1-ylmethyl)-4(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 4h, mp: 156-161° C. (washed with diethylether). ¹H NMR (CDCl₃): δ 1.80-1.095 (m, 1 H); 2.15 (s, 3 H); 2.20-2.35(m, 1 H); 2.45-2.60 (m, 3 H); 2.65-3.00 (m, 5 H); 3.20 (broad s, 2 H);3.30-3.45 (dd, 1 H); 6.05 (broad s, 1 H); 6.95 (t, 2 H); 7.15 (d, 1 H);7.15-7.25 (m, 2 H); 7.35 (dd, 2 H);. 7.50 (s, 1 H)

[0204]4-(4-Fluorophenyl)-1-(6-methansulfonylaminoindan-1-ylmethyl)piperidine4i, mp: 152-155° C. (diethyl ether), ¹H NMR (CDCl₃): δ 1.70-1.90 (m, 5H); 2.00-2.20 (m, 2 H); 2.20-2.35 (m, 1 H); 2.40-2.70 (m, 3 H);2.75-2.95 (m, 2 H); 3.00 (s, 3 H); 3.10 (t, 2 H); 3.25-3.45 (m, 1 H);6.70 (broad s, 1 H); 6.90-7.05 (m, 3 H); 7.15-7.25 (m, 3 H); 7.35 (s, 1H)

[0205]1-(6-Cyclopropylcarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine4j, mp: 134-140° C. (diethyl ether), ¹H NMR (CDCl₃): δ 0.75-0.90 (m, 2H); 1.05-1.15 (m, 2 H); 1.45-1.60 (m, 1 H); 1.75-1.95 (m, 6 H);2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H); 2.35-2.50 (m, 2 H); 2.65 (dd, 1H); 2.70-2.95 (m, 2 H); 3.00-3.15 (m, 2 H); 3.35 (qui, 1 H); 6.95 (,2H); 7.05-7.25 (m, 4 H); 7.40 (broad s, 2 H); 7.65 (broad s, 1 H)

[0206] 1-(6-Cyclopentylcarbonylaminoindan-1-ylmethyl)4-(4-fluorophenyl)piperidine4k, mp: 177-178° C. (diethyl ether). ¹H NMR (CDCl₃): δ 1.50-170 (m, 2H); 1.70-1.95 (m, 1 H); 2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H);2.35-2.50 (m, 2 H); 2.60-2.75 (m, 2 H); 2.75-2.95(m,2 H); 2.95-3.15 (m,2 H); 3.35 (qui, 1 H); 6.95 (t, 2 H); 7.10-7.25 (m,5 H); 7.65 (s, 1 H)

[0207]1-(6-Ethyloxycarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine,fumarate 4l, mp: 191-193° C. (ethanol/acetone 2:1). ¹H NMR (DMSO-d₆): δ1.15 (s, 3 H); 1.07-1.90 (m, 3 H); 2.10-2.30 (m, 3 H); 2.40-2.90 (m, 5H); 3.10-3.20 (m, 2 H); 3.25-3.35 (m, 1 H); 4.15 (q, 1H); 6.60 (s, 1.5H); 7.00-7.15 (m,4 H); 7.35 (dd, 2 H); 7.55 (s, 1 H); 9.45 (s, 1 H).

[0208]4-(4-Chlorophenyl)-1-(6-methansulphonylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyperidine,oxalate 4m, mp: 176-178° C. (from ethanol), ¹H NMR (DMSO-d₆): δ1.90-2.00 (m, 1 HH); 2.30-2.40 (m, 1 H); 2.95 (s, 3 H); 2.65-3.10 (m, 5H); 3.20-3.30 (m, 3 H); 3.50-3.60 (m, 1 H); 3.75 (broad S, 2 H); 6.25(broad s, 1 H); 7.05 (dd, 1 H); 7.15-7.25 (m, 2 H); 7.45 (d, 2 H); 7.55(d, 2 H); 9.60 (broad s, 1 H).

[0209] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-methylphenyl) piperidine4n, mp: 173-175° C. (washed with diethyl ether), ¹H NMR (CDCl₃): δ1.70-1.95 (m, 5 H); 2.10 (s, 3 H); 2.20-2.30 (m, 1 H); 2.30 (s, 3 H);2.35-2.50 (m,2 H); 2.65 (dd, 1 H); 2.70-2.90 (m, 2 H); 3.00-3.15 (m, 2H); 3.35 (qui, 1 H); 7.05-7.25 (m, 6 H); 7.50 (s, 1 H); 7.55 (s, 1 H).

[0210] 1-(6-Acetylaminoindan-1-ylmethyl)-4(3,4-dichlorophenyl)piperazine 4o, mp: 161-163° C. (washed with diethyl ether), ¹H NMR(CDCl₃): δ 1.80-1.90 (m, 1 H); 2.10 (s, 3 H); 2.15-2.30 (m, 1 H); 2.45(dd, 1 H); 2.55-2.70 (m, 5 H); 2.70-3.00 (m, 2 H); 3.20 (t, 4 H); 3.35(qui, 1 H); 6.25 (dd, 1 H); 6.95 (d, 1 H); 7.10 (d, 1 H); 7.20 (dd, 1H); 7.25 (d, 1 H); 7.40 (broad s, 1 H); 7.60(s, 1 H).

[0211] 1-(6-Acetylaminoindan-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, oxalate 4p, mp: 223-226° C. (from acetone), 1H NMR (DMSO-d₆): δ 1.80-1.95 (m, 1 H); 2.05 (s, 3 H); 2.20-2.40 (m, 1H); 2.65-3.00 (m, 5 H); 3.15-3.30 (m, 3 H); 3.50-3.60 (m, 4 H); 3.70(broad s, 2 H); 6.2 5 (broad s, 1 H); 7.15 (d, 1 H); 7.30 (d, 1 H); 7.40(d, 2 H); 7.50 (d,2 H); 7.65 (s, 1 H).

[0212]1-(6-Acetytaminoindan-1-ylmethyl)-4-(3,4-methylendioxypbenyl)piperazine,4q, mp: 188-189° C. (washed witb diethyl ether). ¹H NMR (CDCl₃): δ1.70-1.95 (m, 1 H); 2.15 (s, 3 H); 2.15-2.30 (m, 1 H); 2.45 (dd, 1 H);2.60-2.70 (m, 5 H); 2.70-2.90 (m, 2 H); 3.10 (t, 4 H); 3.40 quin, 1 H);5.85 (s, 2 H); 6.45 (dd, 1 H); 6.55 (d, 1 H); 6.70 (d, 1 H); 7.15 (d, 1H); 7.20-7.35 (m, 2 H); 7.55 (s, 1 H).

[0213]1-(6-Acetylaminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine,hemioxalate, 4r. mp: 163-165° C. (acetone). ¹H NMR (DMSO-d₆): δ1.65-1.95 (m, 3 H); 2.05 (s, 3 H); 2.15-2.30 (m, 3 H); 2.65-3.30 (m, 8H); 3.40-3.50 (m, 1 H); 7.15 (d, 1 H); 7.25 (d, 1 H); 7.70-7.85 (m, 3H); 8.00 (s, 1 H).

EXAMPLE 5 (method a)

[0214] 4-4-Fluoropbenyl)-1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidine, 5a

[0215] 1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl) piperidine, 2a (3g) was dissolved in dichloromethane (140 ml) and methylisyanate (0.53 g)was added. The solution was refluxed for 4 hours. Dichloromethane wasevaporated and the remaining crude title compound was purified by columncromatography on silica gel (eluted with 4% triethylamine in ethylacetate). The pure title compound 5a crystallized from diethyl ether.Yield: 0.8 g, mp: 170-173° C. ¹H NMR (CDCl₃): δ 1.70-1.90 (m, 5 H);2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H); 2.35-2.55 (m, 2 H); 2.60 (dd, 1H); 2.80 (d, 3 H); 2.75-2.95 (m, 2 H); 3.05 (broad d; 2 H); 3.30 (qui, 1H); 4.95 (q, 1 H); 6.55 (s, 1 H); 6.90-7.00 (m, 3 H); 7.10-7.25 (m, 3H); 7.35 (s, 1 H)

[0216] In a similar manner the following urea or thiourea derivativeswere prepared:

[0217]1-[6-(4-Fluorophenyl)aminocarbonylaminoindan-1-ylmethyl]-4-(4-fluorophenyl)-piperidine,5b, mp: 235-238° C. (CH₂Cl₂). ¹H NMR (DMSO-d₆): δ 1.55-1.80 (m, 5 H);2.00-2.30 (m, 3 H); 2.35 (dd, 1 H); 2.45-2.60 (m, 2 H); 2.60-2.85 (m, 2H); 3.05 (broad d, 2 H); 3.30 (qui, 1 H); 7.05-7.15 (m, 6 H); 7.25-7.35(dd, 2 H); 7.40-7.50 (dd, 2 H); 7.55 (s, 1 H); 8.50 (s, 1 H); 8.65 s, 1H)

[0218]4-(4-Fluorophenyl)-1-(6-methylaminothiocarbonylaminoindan-1-ylmethyl)piperidine, fumarate, 5c, mp: 181-183° C. (ethanol/acetone 1:1). ¹H NMR(DMSO-d₆): δ 1.70-1.90 (m, 5 H); 2.15-2.95 (m, 8 H); 2.90 d, 3 H);3.20-3.30 (m, 2 H); 3.40 (qui, 1 H); 6.20 (s, 2 H); 7.05-7.20 (m, 4 H);7.30 (dd, 2 H); 7.40 (s, 1 H); 7.80 (broad s, 1 H); 9.60 (broad s, 1 H).

[0219] 1-(6-Methylaminocarbonylaminoindan-1-ylmethyl)-4-(3,4-methylendioxyphenyl)piperazine, hemioxalate, 5d, mp:132-133° C. (acetone). ¹H NMR (DMSO-d₆): δ 1.70-1.85 (m, 1 H); 2.15-2.30(m, 1 H); 2.60 (d, 3 H); 2.70-3.00 (m, 7 H); 3.20 (m, 4 H); 3.35-3.45(m, 1 H); 5.90 (s, 2 H); 6.00 -6.10 (m, 1 H); 6.40 (dd, 1 H); 6.70 (d, 1H); 6.80 (d, 1 H); 7.05 (d, 1 H); 7.10 (d, 1 H); 7.45 (s, 1 H); 8.40 )(s, 1 H).

EXAMPLE 6 (method a)

[0220]1-(6-Dimethylaminocarbonylaminoindan-1-ylmethyl)-4(4-fluorophenyl)piperidine,6a

[0221] 1-(6-Amiinoindan-1-ylmethyl)-4-(4-fluorophenyl) piperidine, 2a (3g) was dissolved in THF (50 ml) and triethylamine (2 g) was added. At 5°C. dimethylcarbamoylchloride (1 g) in THF (15 ml) was added dropwise.After completed addition the mixture was refluxed for 1.5 hours. THF wasevaporated. Water was added and extraction with dichloromethane (2×50ml) and work-up as above of the combined organic phases yielded crudetitle product, which was purified by column chromatography on silica gel(eluted with 4%. triethylamine in a 1:1 mixture of ethyl acetate andheptane). The pure title compound 6a crystallized from diethyl ether.Yield: 1.4 g, mp: 141-144° C. ¹H NMR CDCl₃): δ 1.65-2.55 (m, 10 H); 2.70(dd, 1 H); 2.70-2.95 (m, 2 H); 2.95-3.05 (m, 1 H); 3.05 (s, 6 H); 3.15(broad d, 1 H); 3.35 (qui, 1 H); 6.25 (s, 1 H); 6.95-7.25 (m, 6 H); 7.45(s, 1 H)

[0222] In a similar manner the following urea and thiourea derivativeswere prepared:

[0223]1-(6-Dimethylaminothiocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine6b, mp: 175-180° C. (washed with diethyl ether). ¹H NMR (CDCl₃): δ1.65-1.95 (m, 5 H); 2.00-2.15 (m, 2 H); 2.20-2.35 (m, 1 H); 2.35-2.55(m, 2 H); 2.60 (dd, 1 H); 2.70-2.90 (m, 2 H); 3.05-3.15 (m, 2 H); 3.85(s, 6 H); 3.40 (qui, 1 H); 6.95-7.10 (m, 4 H); 7.15-7.30 (m, 4 H)

[0224] 4-(4-fluorophenyl)-1-[6-(1-pyrrolidinyl)carbonylaminoindan-1-ylmethyl)piperidine 6e, mp: 190-193° C. (washedwith diethyl ether). ¹H NMR (CDCl₃): δ 1.65-2.55 (m, 14 H); 2.65 (dd, 1H); 2.75-2.90 (m, 2 H); 3.00 (broad d, I H); 3.15 (broad d, 1 H); 3.35(qui, 1 H); 3.45 (t, 4 H); 6.15 (s, 1 H); 6.95 (t, 2 H); 7.00-7.10 (m, 2H); 7.20 (dd, 2 H); 7.50 (s,1 H)

EXAMPLE 7 (method a)

[0225]1-(6-Aminocarbonylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine,hemifumarate, 7a

[0226] A solution of potassium isocyanate (1.5 g) dissolved indichloromethane (20 ml) was cooled to 5° C. and a solution oftrifluoroacetic acid (1.9 g) in dichloromethane (20 ml) was addeddropwise. To the resulting mixture was added dropwise a solution of1-(6-aminoindan-1-ylmethyl)-4-fluorophenyl)piperidine, 2a (3 g) indichloromethane (10 ml). The temperature was allowed to raise to roomtemperature. After stirring for another 3 hours the mixture was pouredon ice (500 g) and diluted aqueous NH₄OH was added until pH>9. Theorganic phase was separated and worked-up as above. The crude titleproduct was purified by column chromatography on silica gel (eluted with4% triethylamine in ethanol/ethyl acetate 1:3). The purified product (2g) was dissolved in acetone (20 ml) and added to a solution of fumaricacid (0.6 g) in ethanol (20 ml). The precipitated hemifumarate salt wasfiltered off and dried. Yield: 1.6 g, mp: 172-174° C. ¹H NMR (DMSO-d₆):δ 1.65-1.90 (m, 5 H); 2.10-2.35 (m, 3 H); 2.45-2.90 (m, 5 H); 3.10-3.25(m,2 H); 3.45 (qui, 1 H); 6.85 (s, 2 H); 6.60 (s, 1 H); 7.00-7.15 (m, 4H); 7.30 (dd, 2 H); 7.45 (s, 1 H); 8.45 (s, 1 H).

EXAMPLE 8

[0227] 5-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 8a

[0228] A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate,hydrochloride (71 g), and potassium hydroxide. (38 g) in ethanol (450ml) was refluxed for 6 hours. After cooling inorganic salts werefiltered off and ethanol evaporated in vacuo. To the remaining oil wasadded brine (500 ml) and ethyl acetate (2×200 ml). Thc organic phase wasseparated and worked-up as above. Yield of crude title product: 45 g(semicrystalline).

[0229] In a corresponding manner the following3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were prepared:

[0230] 6-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 8b

[0231] 5-Fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 8c

EXAMPLE 9

[0232] 5-Chloro-3-(4-piperidinyl)-1H-indole, 9a

[0233] Crude 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole 8a(26 g) was dissolved in glacial acetic acid (330 ml) and PtO₂ (0.7 g)was added. The mixture was hydrogenated in Parr apparatus at 3 atm. for5 hours. The catalyst was filtered off and excess acetic acid evaporatedin vacuo. Water was added and pH was adjusted to >9 by addition ofdiluted aqueous NH₄OH. Extraction with ethyl acetate (2×200 ml) andwork-up of the combined organic phases yielded 19 g of crude titlecompound as a visceous oil.

[0234] In a corresponding manner the following3-(4-piperidinyl)-1H-indoles were prepared:

[0235] 6-Chloro-3-(4-piperidinyl)1H-indole, 9b

[0236] 5-Fluoro-3-(4-piperidinyl)1H-indole, 9c

EXAMPLE 10

[0237]3-[1-(5-Amino-2,3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole,10a

[0238] 5-Nitro-3-benzothiophencarboxylic acid 1b (20 g) was convertedinto the corresponding carboxylic acid chloride as in Example 2. Theacid chloride was dissolved in THF (200 ml) and added dropwise to asolution of 5-chloro-3-(4-piperidinyl)-1H-indole, 9a (19 g) andtriethylamine (10 ml) in THF (200 ml) at 0-5° C. The mixture was stirredovernight at room temperature. THF was evaporated. Water was added tothe remaining oil. Extraction with dichloromethane (2×100 ml) andwork-up of the organic extracts afforded the crude5-nitro-3-benzothiophencarboxylic acid amide, which was subsequentlypurified by column chromatography on silica gel eluted with ethylacetatelheptane 1:1). Yield 6.6 g, mp: 243-230° C. All of the amide wasdissolved in 90% ethanol at reflux. Fe-powder (5 g) and concentratedaqueous HCl were added successively in small portions during 10 minutes.The mixture was refluxed for another 2.5 hours. Inorganic salts werefiltered off and ethanol evaporated in vacuo. Water was added to theremaining oil and pH was adjusted to >9 by addition of diluted aqueousNH₄OH. Extraction with dichloromethane (2×100 ml) and subsequent work-upof the organic phase yielded 4 g of the5-amino-3-benzothiophencarboxylic acid amide as an oil. All of this oilwas dissolved in methanol (100 ml). 0.5 g of Mg turnings were added. Byheating to 35° C. an exothermic reaction started. Mg turnings were addedin small portions (3×0.5 g) while keeping the temperature below 45° C.The mixture was finally poured into an aqueous NH₄Cl solution andconcentrated aqueous HCl (1 ml) was added. Extraction withdichloromethane (2×50 ml) and work-up of the organic extracts as aboveafforded 2 g of the 5-amino-2,3-dihydrobenzothiophen-3-carboxylic acidamide as an oil. To a suspension of LiAIH₄ (0.6 g) in dry THF (50 ml)was added dropwise a solution of all of the carboxamide in THF (50 ml).The mixture was gently refluxed for 2 hours. After cooling to 10° C.water (2.4 ml ) and a 15% aqueous NaOH solution were cautiously added todestroy excess LiAIH₄. Inorganic salts were filtered off and washedextensively with THF. The combined THF solutions were evaporated leaving1.9 g of3-[1-(5-amino-2,3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl)-5-chloro-1H-indoleas an oil.

[0239] In a similar manner the following aniline derivatives wereprepared:

[0240] 3-[1-(5-Amino-2,3-dihydrobenzothiophen-3-ylmethyl)- 1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole, 10b as an oil

[0241] 3-1-(5-Amino-2,3-dihydrobenzothiophen-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-fluoro-1H-indole, 10c as an oil.

[0242] The corresponding 1-(6-Aminoindan-1-ylmethyl)-substituted4-(3-indolyl)piperidines and 4-(3indolyl)-1,2,3, 6tetrahydropyridineswere prepared from the corresponding 1-indancarboxamides, which weresuccessively nitrated in the 6 position, reduction of the nitrosubstituent and reduction of the carboxamide carbonyl group. A reactionsequence as outlined in Example 3. The following indan derivatives wereprepared accordingly:

[0243] 3-[1-(6-Aminoindan-1-ylmethyl)piperidin-4-yl]-5-fluoro-1H-indole,10d as an oil.

[0244] 3-[1-(6-Aminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole,10e as an oil.

[0245]3-[1-(6-Aminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole,10f as an oil.

[0246]3-[1-(6-Aminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,10g as an oil.

[0247] 1-[1-(6-aminoindan-1-ylmetbyl)piperidin-4-yl]-5-chloro-1H-indole,10h as an oil.

EXAMPLE 11

[0248]3-[1-(5-Acetylamino-2,3dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole,oxalate, 11a

[0249] To a solution of3-[1-(5-amino-2.3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole10a (1.9 g) and triethylamine (2 ml) in dichloromethane (50 ml) kept at0° C. was added dropwise a solution of acetylchloride (0.4 g) indichloromethane (10 ml). The mixture was stirred at room temperature for2 hours. Water was added and the organic phase was worked-up as above.The crude title compound was purified by column chromatography on silicagel (eluted with 4% triethylamine in ethyl acetate). Yield : 0.8 g. Theoxalate salt of the title compound crystallized from a 1:1 mixture ofacetone and ethanol. MP: 168-174° C. ¹H NMR (DMSO-d₆): δ 2.00 (s, 3 H);1.95-2.15 (m, 4 H); 2.85-3.25 (m, 5 H); 3.40-3.50 (m, 2 H); 3.55-3.70(m, 2 H); 3.90-4.00 (m, 1 H); 7.00-7.40 (m, 6 H); 7.70 (s, 1 H); 7.70(broad d, 2 H); 9.95 (broad s, 1 H); 11.05 (broad s, 1 H).

[0250] In a similar manner the following indolyl derivatives wereprepared:

[0251]3-[1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole,oxalate 11b, mp: 214-216° C. (ethanol), 1H NMR (DMSO-d₆): δ 2.00 (s, 3H); 2.75 (broad s, 2 H); 2.95-3.40 (m, 5H); 3.50-3.80 (m, 3 H); 3.95(broad s, 1 H); 6.15 (broad s, 1 H); 7.15 (t, 2 H); 7.25 (d, 1 H); 7.45(d, 1 H); 7.60 (s, 1 H); 7.65 (s, 1 H); 7.85 (s, 1 H); 9.95 (s, 1 H);11.50 (s, 1 H)

[0252]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-fluoro-1H-indole,oxalate 11c, mp: 145-149° C. (acetone). ¹H NMR (DMSO-d₆): δ 1.80-2.15(m, 6 H); 2.00 (s, 3 H); 2.30-2.45 (m, 1 H); 2.70-2.90 (m, 2 H);2.95-3.20 (m, 3 H); 3.35 (d, 1 H); 3.50-3.80 (m, 3 H); 6.95 (dt, 1 H);7.15 (d, 1 H); 7.25 (s, 1 H); 7.30 (d, 1 H); 7.40 (dd, 1 H); 7.45 (dd, 1H);7.70 (s, 1 H); 9.95 (s, 1 H); 11.05 (s, 1 H)

[0253]3-[1-(5-Acetylamino-2,3-dihydrobenzothiophen-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-fluoro-1H-indole,oxalate 11d, mp: 155-165° C. (acetone). ¹H NMR (DMSO-d₆): δ 2.00 (s, 3H); 2.75 (broad s, 2 H); 2.95-3.45 (m, 5 H); 3.50-3.80 (m, 3 H); 3.95(broad s, 1 H); 6.15 (broad s, 1 H); 6.95 (t, 1 H); 7.20 (d, 1 H); 7.30(d, 1 H);7.45 (m, 1 H); 7.55-7.70 (m, 3 H); 9.95 (s,1 H); 11.45 (s,1 H)

[0254]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,oxalate hemihydrate 11c, mp: 151-164° C. (acetone). ¹H NMR (DMSO-d₆): δ1.95-2.10 (m, 1 H); 2.00 (s, 3 H); 2.30-2.45 (m, 1 H); 2.70-2.90 (m, 4H); 3.15 (t, 1 H); 3.35-3.50 (m, 3 H); 3.55-3.70 (m, 1 H); 3.95 (broads, 2 H); 6.15 (s, 1 H); 7.05 (dd 1 H); 7.15 (d, 1 H); 7.25 (d, 1 H);7.45 (d, 1 H); 7.55 (d, 1 H); 7.60 (s, 1 H); 7.85 (d, 1 H); 9.95 (s, 1H); 11.55 (s, 1 H)

[0255]3-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-6-chloro-1H-indole,oxalate 11f, mp: 122-130° C. (acetone). ¹H NMR (DMSO-d₆): δ1.90-2.15 (m,6 H); 2.00 (s, 3 H); 2.25-2.40 (m, 1 H); 2.70-3.10 (m, 6 H); 3.35 (d, 1H); 3.45-3.65 (m, 2 H); 7.00 (dd, 1 H); 7.15-7.25 (m, 2 H); 7.30 (d, 1H); 7.40 (s,1 H); 7.60-7.70 (m, 2 H); 9.90 (s, 1 H); 11.05 (s, 1 H)

[0256]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropiridin-4-yl]-5-chloro-1H-indole,oxalate 11g, mp: 220-223° C. (acetone/ethanol 5:1). ¹H NMR (DMSO-d₆):δ1.95-2.10 (m, 1 H); 2.00 (s, 3 H); 2.30-2.45 (m, 1 H); 2.70-2.95 (m, 4H); 3.10 (t, 1 H); 3.30-3.45 (m, 3 H); 3.55-3.70 (m, 1 H); 3.85 (broads, 2 H); 6.15 (s, 1 H); 7.10-7.20 (m, 2 H); 7.30 (d, 1 H); 7.45 (d, 1H); 7.60-7.70 (m, 2 H);7.85 (s, 1 H); 9.90 (s, 1 H); 11.50 (s, 1 H);

[0257]1-[1-(6-Acetylaminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole,11 h, mp: 189-191° C. (ethyl acetate). ¹H NMR (CDCl₃): δ1.80-2.00 (m, 1H); 2.05-2.40 (m, 7 H); 2.20 (s, 3 H); 2.50 (dd,1 H); 2.65 (dd, 1 H);2.80-2.95 (m, 2 H); 3.15 (broad t, 2 H); 3.35 (quin, 1 H); 4.20-4.30 (m,1 H); 6.45 (d, 1 H); 7.20-7.35 (m, 4 H); 7.30-7.40 (m, 2 H); 7.60 (d, 1H); 7.70 (broad s, 1 H).

EXAMPLE 12 (method e)

[0258]4-(4-Fluorophenyl)-1-[6-(1-pyrrolidin-2-onyl)indan-1-ylmethyl]piperidine,fumarate, 12a

[0259] To a solution of1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) andtriethylamine (2 ml) in dichloromethane (50 ml) at 0° C. was addeddropwise a solution of 4-chlorobutyric acid chlorid (1.4 g) indichloromethane (15 ml). The mixture was finally stirred for 5 hours atroom temperature. Ice cold diluted aqueous NaOH solution was added andthe organic phase was subsiquently worked-up as above. The crude1-[6-(4-chlorobutanoylamino)indan-1-ylmethyl]-4-(4-fluorophenyl)-piperidinewas purified by column chromatography on silics gel (eluted with 4%triethylamine in a 1:3 mixture of ethyl acetate and heptane). Yield ofcrystalline product: 2.4 g with mp: 129-135 (washed with diethyl ether).A solution of the thus isolated 4-chlorobutanoyl derivative (1 g) andpotassium tert-butoxide (0.4 g ) in dry THF (40 ml) was refluxed for 2hours. THF was evaporated in vaccuo. Deluted aqueous NH₄OH anddichloromethane were added and the organic phase was subsequentlyworked-up as above. The remaining oil (1 g) was dissolved in acetone (10ml) and added to a hot solution of fumaric acid (0.3 g) in ethanol (15ml). After cooling in a refrigerator overnight the precipitatedfurmarate salt was filtered off and dried. Yield: 0.7 g, mp: 177-179° C.¹H NMR (DMSO-d₆): δ1.70-1.90 (m, 5 ); 2.10 (qui, 2 H); 2.20-2.40 (m, 3H); 2.45-2.65 (m, 4 H); 2.70-2.95 (m, 3 H); 3.20 (broad t, 2 H); 3.40(qui, 1 H); 3.70-3.90 (m, 2 H); 6.60 (s, 2 H); 7.15 (t, 2 H); 7.20 (d, 1H); 7.30 (dd, 2 H); 7.40 (dd, 1 H); 7.65 (s, 1 H).

EXAMPLE 13

[0260] (+)-6-Nitro-1-indancarboxylic acid, 13a

[0261] A solution of 6-nitro-1-indancarboxylic acid (1a) (96 g) andbrucine dihydrate (200 g) was heated in acetone (1.25 L) until a clearsolution was obtained. The solution was left in a refrigeratorovernight. The precipitated brucine salt was filtered off. Yield 159.1g. Recrystallization from 2-propanol afforded 103 g of pure(+)-6-1-indancarboxylic acid brucine salt. The salt was dissolved inwater and diluted hydrochloric acid was added. Extraction with diethylether and work-up as above afforded 29.8 g of 13a. Mp: 92-94° C.[Ε]_(D)=+83.3° (c=1, methanol).

EXAMPLE 14

[0262] (+)-1-Acetylaminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine14a

[0263] The (+)-enantiomer of compound 4a was prepared from(+)-6-Nitro)-1-indancarboxylic acid, 13a according to the methods inExamples 2 and 4. Mp: 145-146° C. ¹H NMR (CDCl₃): δ 1.70-1.90 (m, 5 H);2.00-2.15 (m, 1 H); 2.15 (s, 3 H); 2.20-2.30 (m, 1 H); 2.35-2.50 (m, 2H); 2.60 (dd, 1 H); 2.70 -2.90 (m, 2 H); 2.95-3.15 (m, 2 H); 3.45 (qui,1 H); 6.95 (t, 2 H); 7.05-7.25 (m, 5 H); 7.55 (s, 1 H). [α]_(D)=+24.3°(c=1, methanol).

EXAMPLE 15

[0264]3-[1-(6-Acetylaminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1-methyl-1H-indole15a

[0265]3-[1-(6-nitroindan-1-ylkarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole(23 g), prepared according to the procedure in Example 10, was dissolvedin dry DMF (300 ml) and potassium tert-butoxide (7.3 g) was added at 10°C. Methyliodide (23.2 g) was added dropwise during 30 min. The mixturewas left at room temperature overnight. Water and diethyl ether wereadded and the organic phase was worked-up as above. The crudeN-methylated indole was purified by column chromatography on silica gel(eluted with a 1:1 mixture of ethyl acetate and heptane). Yield 2.75 g.Reduction of the nitro group with Fe in 90% acidic ethanol, followed byreduction of the amide carbonyl group and finally acetylation of theanilino group according to the methods in Examples 10 and 11 affords thetitle compound 15a. Mp: 189-193° C. (washed with diethyl ether). ¹ NMR(CDCl₃): δ 1.80 (broad s, 1 H); 1.80-1.95 (m, 1 H); 2.10 (s, 3 H);2.25-2.40 (m, 1 H); 2.50-2.60 (m, 3 H); 2.70-2.95 (m, 5 H); 3.25 (broads, 2 H); 3.40 (qui, 1 H); 3.70 (s, 3 H); 6.15 (broad s, 1 H); 7.00 (s, 1H); 7.10 (dd, 1 H); 7.15 (d, 1 H); 7.20-7.30 (m, 3 H); 7.50 (s, 1 H);7.80 (d, 1 H).

[0266] Catalytic hydrogenation of compound 15a according to the methodin Example 9 afforded:

[0267]3-[1-(6-Acetylaminoindan-1-ylmethyl)pipeddin-4-yl]-6-chloro-1-methyl-1H-indole,oxalate 15b, mp: 202-205° C. (acetone). ¹H NMR (DMSO-d₆): δ 1.90-2.15(m, 5 H); 2.00 (s, 3 H); 2.30-2.40 (m, 1 H); 2.70-3.15 (m, 6 H); 3.35(d, 1 H); 3.50-3.70 (m, 2 H); 3.75 (s, 3 H); 7.00 (dd, 1 H); 7.10-7.30(m, 3 H); 7.55 (d, 1 H); 7.65 (s, 1 H); 7.65 (d, 1 H); 9.90 (s, 1 H).

EXAMPLE 16 (Method f)

[0268] 4-(4-Fluorophenyl)-1-(6-methylaminoindan-1-ylmethyl)piperidine,1.5 oxalate 16a

[0269] To a solution of4-(4-fluorophenyl)-1-(6-methylaminoindan-1-ylmethyl)piperidine, 2a (4 g)and triethylamine (3 ml.) in dichloromethane was added dropwise at 0-5°C. a solution of ethyl chloroformate (1.5 g) in dichloromethane (1.5ml.). Thc mixture was stirred at room temperature for 2 hours and pouredonto saturated brine (500 ml.). The organic phase was separated andworked-up as previously. Yield of the ethyl carbamate as an oil 4.3 g.To a suspension of LiAIH₄ (1.2 g) in dry diethyl ether (20 ml.) at 5° C.was added dropwise a solution of all of the ethyl carbamate in dry THF(25 mL). The mixture was stirred for an additional hour at 5° C. andfinally at room temperature for 5 hours. Excess of LiAIH₄ was destroyedby cautiously adding water and diluted aqueous NaOH solution (6 mL).Precipitated inorganic salts were filtered off and the solventsevaporated in vacuo. The crude title compound was purified by columnchromatography on silica gel (eluted with a 1:1 mixture of heptane andethyl acetate). Yield as an oil 1.5 g. The 1.5 oxalate salt 16acrystallized from a 1:1 mixture of acetone and ethanol. Mp: 84-86° C. ¹HNMR (DMSO-d₆): δ 1.75-2.10 (m, 5 H); 2.20-2.40 (m, 1 H); 2.60 (s, 3 H);2.60-2.90 (m, 3 H); 3.00-3.15 (m, 3 H); 3.40-3.80 (m, 4 H); 6.40 (dd 1H); 6.50 (d, 1 H); 6.95 (d, 1 H); 7.15 (t, 2 H); 7.35 (d, 1 H)

EXAMPLE17

[0270] 5-Chloro-1-(4-piperidinyl)-1H-indole, 17a

[0271] To a solution of 5-chloro-1H-indole (20 g) inN-methyl-2-pyrrolidione (450 mL) were added potassium carbonate (82 g),CuBr (7.5 g), and Cu bronze (3 g). The mixture was heated to 140° C. and4-bromopyrinde, hydrochloride (22 g). The mixture was heated for 1 hourat 150° C. and further 4-bromopyridine, hydrochloride (15 g) was added.This procedure was repeated twice and the mixture was finally heatedovernight at ₁₅₀° C. After cooling precipitated inorganic salts werefiltered off. Water (2 L), ethyl acetate (500 mL), and diluted aqueousammonia (200 mL) were added. Undissolved material was filtered off- anddiscarded. The organic phase was worked-up as above affording 34 g of5-chloro-1-(4-pyridyl)-1H-indole with mp: 153-155° C. All of thisproduct, without further purification, was dissolved in dimethoxyethane(350 mL) at 60-70° C. Methyliodide (14 mL) was added and the mixture washeated at reflux for 7 hours. After cooling the precipitated quaternizedpyridinium salt was filtered off and washed with dimethoxyethane. Yield32 g. Mp: 257-260° C. All of the pyridinium salt was suspended inethanol (450 mL) and water (50 mL). NaBH₄ (16 g) was added in smallportions during 1.5 hours with stirring. After stirring for another 1.5hours most of the ethanol was evaporated at room temperature in vacuo.Ethyl acetate (300 mL) and water (500 mL) were added and the organic waswas worked up as previously. Yield of5-chloro-1-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 17g Isan oil. To a solution of the tetrahydropyridinyl (15 g) derivative inglacial acetic acid. (150 mL) was added PtO₂ and the mixture washydrogenated in a Parr apparatus at 3 ato for 7 hours. The catalyst wasfiltered off, most of the acetic acid evaporated in vacuo and finallythe crude 5-chloro- 1-(1-methyl-4-piperidinyl)-1H-indole was extractedwith ethyl acetate from an alkaline aqueous solution. Yield 13 g as anoil. Any remaining water in this crude product (10 g) was removed byevaporation with toluene. Finally the oil was dissolved in1,1,1-trichloroethane (200 mL). At reflux temperature2,2,2-trichloroethyl chloroformate (6.5 mL) dissolved in1,1,1-trichloroethane (20 mL) was added dropwise. The mixture wasrefluxed for another 2 hours, sodium carbonate (2 g) was added andreflux continued for 0.5 hours. After cooling the mixture was filteredthrough silica gel (eluted with dichloromethane). Yield 10 g of crudecarbamate derivative. To a solution of the carbamate (6 g) in 90%aqueous acetic acid (110 mL) was added finely powdered Zn (12 g) insmall portions at 45° C. during 1 hour. The mixture was heated foranother hour at 50° C., Zn-salts were filtered off and most of theacetic acid evaporated in vacuo. The remaining oil was dissolved inwater (200 mL) and ethyl acetate (200 mL). The pH of the aqueous phasewas adjusted >9 by adding diluted aqueous ammonia. The organic phase wasfinally worked-up as previously yielding 3.5 g of crude title product17a as an oil which was used without further purification to preparecompound 10h.

EXAMPLE18

[0272]1-(6-Acetylaminoindan-1-ylmethyl)-4-acetyloxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine,18a.

[0273] To a solution of1-(6-aminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine,2j, (6.7 g) and triethylamine (4 mL) in dichloromethane (100 mL) wasadded dropwise at 0-5° C. a solution of chloroacetylchloride (2.6 mL) indichloromethane (50 mL). The mixture was stirred overnight at roomtemperature. Water was added and pH was adjusted to >9. The organicphase was separated and worked up as previously. The crude product waspurified by column chromatography on silica gel (eluted with 4%triethylamine in ethyl acetate). Yield of pure 18a 6.2 g as an oil.

EXAMPLE 19

[0274]5-Chloro-1-[1-(6-methylaminocarbonylaminoindan-1-ylmethyl)piperidin-4-yl]-1H-indole,19a.

[0275] To a solution of 1-[1-(6-aminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole, 10h (0.9 g) in dichloromethane (10mL) was added methylisocyanate (0.2 mL). The mixture was stirred at roomtemperature for 16 hours. Dichloromethane was evaporated. Upon additionof ethyl acetate the title compound 19a crystallized. The crystallineproduct was filtered off and dried overnight at 80° C. in vacuo. Yield0.6 g. mp: 193-195° C. ¹H NMR (DMSO-d₆): δ 1.70-1.85 (m, 1 H); 1.90-2.35(m, 7 H); 2.35-2.85 (m, 4 H); 2.65 (d, 3 H); 3.05-3.15 (m, 2 H); 3.25(quin, 1 H); 4.35-4.45 (m, 1 H); 5.95 (dt, 1 H); 6.45 (d, 1 H);7.00-7.20 (m, 3 H); 7.50-7.65 (m, 4 H); 8.35 (s, 1 H).

Pharmacological Testing

[0276] The compounds of the invention were tested in well recognized andreliable methods. The well-known 5-HT_(2A) antagonist MDL 100,907 andthe well-known 5-HT_(1A) antagonist buspirone were included in the testsas reference compounds. The tests were as follows, and the results aregiven in the following Table 1.

[0277] Inhibition of ³H-8-OH-DPAT Binding to Serotonin 5-HT_(1A)Receptors in Rat Brain in vitro.

[0278] By this method the inhibition by drugs of the binding of the5-HT_(1A) agonist ³H-8-OH-DPAT (1 nM) to 5-HT_(2A) receptors inmembranes from rat brain minus cerebellum is determined in vitro.Accordingly, this is a test for affinity for the 5-HT_(2A) receptor. Thetest is performed as described by Hyttel et al., Drug. Dev. Res., 1988,15, 389-404.

[0279] Inhibition of ³H-Ketanserin Binding to 5-HT₂ Receptors in RatCortex in vitro.

[0280] By this method the inhibition by drugs of the binding of³H-Ketanserin (0.5 nM) to 5-HT_(2A) receptors in membranes from rat isdetermined in vitro. The method is described in Hyttel, Pharmacology &Toxicology. 61, 126-129, 1987. TABLE 1 Binding Data (IC₅₀ values in nMor % inhibition of binding at 100 nM) Compound No ³H 8-OH DPAT(5-HT_(1A)) ³H Ketanserin (5-HT_(2A))  2a 480. 2.5  2h 19%/100. 4.1  4n11. 4.0  4b 21. 2.9  4c 28. 2.3  4d 12. 5.0  4e 38. 5.0  4f 84. 65.  4g31. 280.  4h 11. 2.8  4i 500. 2.1  4j 45. 15.  4k 240 30.  4l 26%/10055.  4m 120. 2.7  4n 27. 3.9  4o 11. 51.  4p nt nt  5a 35 5.1 5b >100.000 37.  5c >1000. 3.9  6a 1200 9.1  6b 1200 6.7  6c 8200 9.9 7a 13. 2.6 11a 28. 42. 11b 21. 44. 11c 16. 15. 11d 29. 15. 11e 27. 130.11f 8.0 21. 11g 26. 180. 12a 340 3.5 14a 120. 16. 15a 91. 25%/100 15b15%/100 300. 16a 170. 1.6 buspirone 41. 1300. MDL 100.907 nt^(a) 0.51

[0281] In addition to the above tests, the compounds of the inventionwere tested with respect to affinity for the dopamine D₂receptor bydetermining their ability to inhibit the binding of ³H-spiroperidol toD₂ receptors by the method of Hyttel et al, J. Neurochem., 1985, 44,1613. Furthermore, they were tested with respect to their 5-HT reuptakeinhibiting effect by measuring their ability to inhibit the uptake of³H-serotonin in rat brain synapsomes in vitro by the method described byHyttel and Larsen, Acta Pharmacol. Tox., 1985, 56, suppl. 1, 146-153.

[0282] In general, the compounds of the invention have been foundpotently to inhibit both the binding of tritiated8-hydroxy-2-dipropylaminotetralin (8-OH -DPAT) to 5-HT_(1A) receptorsand the binding of ³H ketanserin to 5-HT_(2A) receptors in vitro. Somecompounds only bind to one of the two serotonin receptor subtypes,5-HT_(1A) or 5-HT_(2A). In addition to these affects, a number of thecompounds have proven to have the further advantage of a potent 5-HTreuptake inhibiting effect. So, for example the compound wherein R¹ isacetyl, R² is H and Ar is 3-indolyl substituted with halogen in the6-position or 5-position or compounds wherein Ar is phenyl substitutedwith Cl in the 4-position show IC₅₀ values in the lower nanomolar range(1-65 nM).

[0283] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep.

Formulation Examples

[0284] The pharmaceutical formulations of the invention may be preparedby conventional method in the art.

[0285] For example: Tablets may be prepared by mixing the activeingredient with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents comprise: corn starch, potato starch, talcum,magnesium stearate, gelatine, lactose, gums, and the like. Any otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients.

[0286] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a pan of the solvent for injection,preferably sterile water, adjusting the solution to desired volume,sterilizalion of the solution and filling in suitable ampules or vials.Any suitable additive conventionally used in the art may be added, suchas tonicity agents, preservatives, antioxidants, etc.

[0287] Typical examples of recipes for the formulation of the inventionare as follows:

[0288] 1) Tablets containing 5.0 mg of Compound 4a calculated as thefree base: Compound 4a 5.0 mg Lactose 60 mg Maize starch 30 mgHydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mgCroscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

[0289] 2) Tablets containing (0.5 mg of Compound 4d calculated as thefree base: Compound 4d 0.5 mg Lactose 46.9 mg Maize starch 23.5 mgPovidone 1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose SodiumType A 1.8 mg Magnesium stearate 0.63 mg

[0290] 3) Syrup containing per milliliter: Compound 11f 25 mg Sorbitol500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mgPropyl-paraben 0.1 mg Ethanol 0.005 mg Flavour 0.05 mg Saccharin natrium0.5 mg Water ad 1 ml

[0291] 4) Solution for injection containing per milliliter: Compound 4a0.5 mg Sorbitol 5.1 mg Acetic acid 0.08 mg Water for injection ad 1 ml

What is claimed is:
 1. A 4-aryl-1-(indanmethyl ordihydrobenzothiophenemethyl)-piperazine compound of Formula I

wherein one of X and Y is CH₂ and the other is selected from the groupconsisting Of CH₂ and S; Z is N; Ar is selected from the groupconsisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl,2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-indol-2-onyl,3-indol-2-onyl, 3-benzofuranyl,3 2-benzothiophenyl, 3-benzothiophenyl,1-naphthyl, and 2-naphthyl, wherein each Ar group can be optionallysubstituted with halogen, lower alkyl, lower alkoxy, lower alkylthio,hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl,trifluromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower-alkyl, nitro,amino, lower alkylamino, di-lower alkylamino, acylamino wherein saidacyl moiety is selected from the group consisting of formyl, lower alkylcarbonyl, cycloalkyl carbonyl, and cycloalkyl-lower alkyl or C₁₋₂alkylenedioxy; R¹ is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkynyl, cycloalk(en) yl,cycloalk(en)yl-lower alk(en/yn)yl, phenyl, phenyl-lower alkyl, acylselected from the group consisting of formyl, lower alkyl carbonyl,cycloalkyl carbonyl, and cycloalkyl-lower alkyl carbonyl, thioacylwherein said acyl moiety is selected from the group consisting offormyl, lower alkyl carbonyl, cycloalkyl carbonyl, and cycloalkyl-loweralkyl, lower alkylsulfonyl, trifluoromethilsulfonyl, and phenylsulfonyl;or R¹ is a group R₉VCO— where V it O or S and R⁹ is lower alkyl,cycloalkyl, cycloalkyl-lower-alkyl or phenyl, or R¹ is a groupR¹⁰R¹¹NCO— or R¹⁰R¹¹NCS— wherein R¹⁰ and R¹¹ are independently selectedfrom the group consisting of hydrogen, lower alkyl, cycloalkyl,cycloalkyl-lower-alkyl and phenyl, or R¹⁰ and R¹¹ taken together withthe N-alom to which they are linked, form a pyrrolidinyl, piperidinyl orperhydroazepin group; R² is hydrogen, lower alkyl, cycloalkyl orcycloalkyl-lower-alkyl; or R¹ and R² taken together with the N-atom towhich they are linked form a group,

wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH₂; and m is 1-4,inclusive; R³-R⁴ are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkylcarbonyl, phenylcarbonyl,halogen substituted phenylcarbonyl, lower alkoxy, lower alkylthio,hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl,cycloalkyl-lower-alkyl and nitro; R⁶ and R⁷ are each hydrogen or loweralkyl or they can be linked together to form a 3-7 membered carbocyclicring; R⁸ is hydrogen or lower alkyl; wherein any alkyl, cycloalkyl orcycloalkylalkyl group present can be optionally substituted with one ortwo hydroxy groups, which can be optionally esterified with an aliphaticor aromatic carboxylic acid; and any aryl substituent present can beoptionally substituted with halogen, lower alkyl, lower alkoxy, loweralkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl.trifluoromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower-alkyl or nitro;or a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound of claim 1, wherein X is CH₂ or S and Y is CH₂.
 3. A Compoundof claim 1, wherein R¹ is acyl selected from the group consisting offormyl, lower alkyl carbonyl, cycloalkyl carbonyl, and cycloalkyl-loweralkyl carbonyl, lower alkyl, lower alkyl sulfonyl, a group R¹⁰R¹¹NCO— orR₁₀R₁₁NCS— wherein R¹⁰ is hydrogen, lower alkyl, cycloalkyl,cycloalkyl-lower-alkyl or phenyl and R¹¹ is hydrogen or lower alkyl orR¹⁰ and R¹¹ taken together with the N-atom to which they are linked forma pyrrolidinyl, piperidinyl or perhydroazepin group.
 4. A compound ofclaim 3, wherein R¹ is formyl, acetyl, methylaminocarbonyl,methylaminothiocarbonyl, dimethylamino-carbonyl,dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl,cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or4-fluorophenylaminocarbonyl.
 5. A compound of claim 1, wherein R² ishydrogen or lower alkyl.
 6. A compound of claim 1, wherein R¹ and R² arelinked together to form a 5-7 membered unsubstituted ring or apyrrolidinyl, piperidinyl or perhydroazepin ring.
 7. A compound of claim1, wherein R³-R⁵ are hydrogen, fluoro, chloro, bromo, methyl,trifluoromethyl or acetyl and R⁶-R⁸ are hydrogen.
 8. A compound of claim1, wherein Ar is phenyl. 3-indolyl, 1-indolyl, or pyrimidyl substitutedwith halogen.
 9. A compound of claim 1, wherein R¹ is acetyl, R² is Hand Ar is 1-indolyl, 2-indolyl, 3-indolyl or phenyl substituted withhalogen.
 10. A compound of claim 9, wherein Ar is 3-indolyl substitutedin the 5-position or 6-position with chloro, fluoro, or phenylsubstituted in the 4-position with chloro.
 11. A pharmaceuticalcomposition comprising one or more compounds of claim 1 in atherapeutically effective amount and in combination with one or morepharmaceutically acceptable carriers or diluents.